Bull. Org. mond. Santa 1973, 48, 1-13 Bull. Wld Hlth Org. The epidemiology of favism MARK A. BELSEY 1 Favism is a potential obstacle to the use ofthefava bean in the development ofa locally produced, inexpensive weaning foodfor the Middle East and North Africa. The purposes of this study were to define the epidemiology offavism, to evaluate the advisability ofusing the fava bean in a weaningfood, and to suggest ways ofavoiding or eliminating the toxic factor in the bean. Field observations, locally acquired data, and a literature review suggested that the use ofthe fava bean in a weaningfood wouldbe hazardous, but that the hazard might be overcome by using certain strains ofthe bean or, moreparticularly, by using old dried beans. The disease is usually directly related in time to the harvesting and availability offresh beans, but it is also associated with fresh dried beans. On the basis ofthe age distribution of the disease, patterns of bean consumption, and local food taboos it appears that the toxic factor is concentrated in the skin of the bean, that it is heat-stable, that in dried beans it decreases with age, and that it crosses into the breast milk of lactating mothers. It also appears that disease expression may be a result of the interaction of several host factors, such as nutritional status and the consumption of other foods. These observations are consistent with the results oflaboratory studies, which incriminate vicine, divicine, andDOPA in the etiology offavism. In order to provide an adequate source of protein intended to define the potential effect of favism on a for infants and children, a combination of a cereal nuttition programme based on the use of a weaning grain and broad beans (Vicia fava) has been sug- food containing V. fava. A second purpose is to gested as a weaning food for use in the Middle East describe and relate the epidemiology of favism to and North Africa, where both wheat and broad laboratory and clinical studies, thereby seeking clues beans are grown extensively. Although the fava bean to the approach to be taken in preventing the disease. is low in methionine content it is rich in lysine (Aykroyd & Doughty, 1964), and can thus compen- sate for the low level of lysine in wheat (FAO, 1955). DESCRIPTION OF THE DISEASE However, there are potential risks in so using the Clinical description fava bean. Some individuals who eat or are exposed to it are reported to develop an acute haemolytic Favism is characterized most often by four signs anaemia, favism. The disease may be fatal, usually and symptoms: weakness or fatigue, pallor, jaundice, occurs in children (especially males), and is gener- and haemoglobinuria. The symptoms are distinct ally thought to be related to the genetic deficiency enough to be recognized as characterizing a specific of erythrocyte glucose-6-phosphate dehydrogenase disease entity among populations experiencing the (1.1.1.49) (G6PD). Favism therefore must be viewed disease. Five different forms of the disease, based on as a potential obstacle to this solution to the problem the degree of severity, have been described by Gas- of malnutrition in the Middle East and North Africa. barrini (1915). In some areas the disease itself is a major public The interval between exposure to the fava bean health problem (Donoso et al., 1969). and the onset of symptoms may be only a few hours The following review and field investigation of and is usually under 24 h in both clinical and favism in the Middle East and North Africa is experimental studies, but it may be as long as several days (Panizon & Vullo, 1961). In contrast, the 1Associate Professor of Epidemiology and Pediatrics, interval between drug exposure and haemolysis in Tulane University, New Orleans, La., USA. Present address: Human Reproduction, World Health Organization, 1211 the G6PD-deficient individual is several days (Burka Geneva 27, Switzerland. et al., 1966; Dern et al., 1954). 2971 - 1- 2 M. A. BELSEY Favism has been observed among individuals who patients with symptoms severe enough to necessitate had previously consumed fava beans without show- blood transfusion are hospitalized, the " true " distri- ing signs or symptoms of the disease; others have bution of either erythrocyte counts or haemoglobin developed the disease on the first exposure (Kattamis levels among all patients with haemolysis following et al., 1969; Angelov & Andrev, 1959). In Egypt most fava bean exposure is not known. of the cases occur among infants on their first Urinary findings are frequent in hospitalized pa- exposure to the bean, which is reflected in the high tients. Haemoglobin is found in large amounts in the proportion of cases among children under 1 year old urine for 1-3 days; more prolonged haemoglobinuria (Ghafsarpur, personal communications). These later is not usually observed. Small amounts of oxy- reports do not support the hypothesis of Kantor & haemoglobin and methaemoglobin are noted in the Arbesman (1959) that favism represents in part a urine, which appears dark brown, red, or even black. hypersensitivity phenomenon among individuals Oliguria and even anuria may occur in severe cases, who have previously ingested or been exposed to the with concomitant azotaemia. Death may occur from bean. renal failure. Repeated attacks of favism are not uncommon; The G6PD level of patients with favism is gener- second attacks of favism were noted in 10 of 120 ally low even during the acute episode (Kattamis et patients studied by Kattamis et al. (1969). No note of al., 1969; Larizza et al., 1958; Russo & Balsamo, repeated attacks has ever been made in the same year 1962). The G6PD deficiency has also been noted in in any of the reported studies or personal communi- the granulocytes of patients with favism (Ideo et al., cations, although a history of annual overt attacks or 1965). Nearly all studies on patients with favism compatible symptoms was elicited from villagers and indicate that there is a low level of reduced gluta- physicians in Egypt, Iran, and Tunisia. thione (GSH) and instability of GSH on in vitro Family clustering of cases is noted, both among incubation with I-acetyl-2-phenylhydrazine (San- the sporadic cases (Vince-Ribaric, 1962; Gehrmann sone & Segni, 1956). et al., 1963) and in larger series. Kattamis et al. In the Mediterranean type of G6PD deficiency (1969) noted the frequent occurrence of mild com- young erythrocytes appear to be almost as deficient pensated symptoms in mothers at the time their male of G6PD as old erythrocytes. During haemolytic children developed favism. crises among Caucasians with G6PD deficiency, the An acute haemolytic anaemia with symptoms GSH instability of surviving erythrocytes is not identical to those in favism was ascribed by Lederer decreased, nor is the GSH significantly increased (1925) to an infectious process before the G6PD (Zannos-Mariolea & Kattamis, 1961). This observa- defect was known. Subsequent writers have specu- tion contrasts with that made among primaquine- lated that many of the cases described as Lederer's sensitive 1 G6PD-deficient Negroes, in whom the anaemia actually were cases of favism in which a continued administration of primaquine results in a history of V. fava ingestion was not specifically asked younger population of erythrocytes with a higher for, was unknown, or was denied despite actual G6PD level (Kellermeyer et al., 1961). Other studies ingestion (Gelin, 1952; Wharton & Duesselman, among patients with favism indicated a fall in 1947). Other cases of Lederer's anaemia may repre- GSH during haemolytic crises, but a later rise sent drug exposure or infection superimposed on of GSH (Panizon & Pujatti, 1958). G6PD deficiency (Burka et al., 1966). Genetics of G6PD deficiency Laboratory finding, The G6PD deficiency is clearly inherited as a sex- Laboratory findings in favism reflect the underly- linked trait. This has been demonstrated in mammals ing G6PD defect, the haemolytic anaemia, and its other than man (Trujillo et al., 1965). Marked consequences. They may also reflect the severity of variability occurs in the phenotypic expression of the the G6PD deficiency, the dose and form of fava bean female heterozygotes (Beutler, 1968). This variability exposure, and the acuteness and severity of the has been explained by the observation that one anaemia. X chromosome is euchromatic, whereas the other is Erythrocyte counts are markedly diminished heterochromatic and genetically inactive (Ohno et among the hospitalized patients, most being between al., 1959). Since the pattern of X-linked inheritance 1 and 2 million cells per mm3 (Kattamis et al., 1969; 1 Primaquine is 8-[(4-amino-1-methylbutyl)amino]-6- Joannides, 1952; Messerschmitt et al., 1967). Since methoxyquinoline. FAVISM 3 precludes the possibility that an inactive X chromo- from areas where falciparum malaria is highly en- some was derived either from the paternal X or the demic, e.g., Iraq and Iran (Shaker et al., 1966). maternal X exclusively, it would be necessary to assume the existence of mosaicism in which the G6PD and haemolysis paternal X was inactive in some cells and the mater- The mechanism of haemolysis in individuals ex- nal X in others (Beutler et al., 1962). In effect, the posed to V. fava or to certain drugs was elaborated female heterozygote possesses two populations of by Sansone & Segni (1956), who showed that a erythrocytes. Techniques for detecting such hetero- lowered reduced glutathione (GSH) level was found geneous populations of cells have been developed in patients who had had favism or acute drug- (Beutler et al., 1963) and heterozygous females have induced haemolytic anaemia. Carson et al. (1956) been shown to have a varying pattern of erythrocyte showed that the erythrocytes of individuals with a staining reflecting such heterogeneity; all the ery- primaquine-sensitive haemolytic anaemia had low throcytes of homozygous subjects fail to stain levels of G6PD.